2, 3-benzodiazepine derivatives and pharmaceutical compositions containing the same as the active ingredient

ABSTRACT

The invention refers to novel 2,3-benzodiazepine derivatives of formula (I) and pharmaceutical compositions containing the same as the active ingredient. The novel compounds antipasmodic, muscle relaxant and neuroprotective activities. In formula I; X represents a hydrogen atom, a chloro atom or a methoxy group; Y stands for a hydrogen atom or a halo atom; Z means a methyl group or a chloro atom; R is a C 1-4  alkyl group or a group of the formula —NR 1 R 2 , wherein R 1  and R 2  represent, independently, a hydrogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group or a C 3-6  cycloalkyl group.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/HU01/00151 which has an Internationalfiling date of Dec. 19, 2001, which designated the United States ofAmerica.

FIELD OF THE INVENTION

The invention refers to novel 2,3-benzodiazepine derivatives andpharmaceutical compositions containing the same as the activeingredient. Due to their non-competitive AMPA antagonist effect, thenovel compounds have antispasmodic, muscle relaxant and neuroprotectiveactivities.

BACKGROUND OF THE INVENTION

The most important stimulant neurotransmitter of the central nervoussystem consists of glutamic acid. The neurotransmitter receptors ofglutamic acid can be divided into two groups: ionotropic receptors (i.e.receptors connected with an ionic channel) and metabotropic receptors.The ionotropic receptors take part in nearly each process of the centralnervous system, for example in the processes of learning, in any type ofmemory, in processes accompanied by acute and chronic neuro-degeneration(or cellular destruction). The ionotropic receptors have role in painsense, motoric function, urination reflex and cardiovascularhomeostasis, too.

Two types of ionotropic stimulant receptors exist: the NMDA and theAMPA/kainate receptors. The receptors of AMPA/kainate type are,primarily, responsible for the so called fast synaptic processes, whilethe NMDA receptors regulate the slow synaptic processes prepared by thefast synaptic ones. Thus, antagonists of the AMPA/kainate receptors mayhave an indirect influence on the function of the NMDA receptors.Consequently, several processes of the central nervous system and thewhole organism can be regulated by the antagonists of the AMPA/kainatereceptors.

Two types of AMPA/kainate receptor antagonists exist: competitive andnon-competitive antagonists. Because of the different character ofinhibition, non-competitive antagonists are preferred to the competitiveantagonists. The first representative of the non-competitive antagonistswas 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepinesynthetized about 15 years ago. Since the discovery of this compoundnumerous 2,3-benzodiazepines having non-competitive AMPA/kainate effecthave been prepared [Donevan, S. D. et al., J. Pharmacol. Exp. Ther.,271, 25–29 (1994); Vizi, E. S. et al., CNS Drug Reviews, 2, 91–126(1996)].

The therapeutical use of 2,3-benzodiazepines having non-competitiveantagonist effect on the AMPA/kainate receptor is extremely various.They can be employed as a neuroprotective agent in case of differentacute and chronic symptoms accompanied by neurodegeneration (Parkinson'sdisease, Alzheimer's disease, stroke etc.), furthermore for theimprovement of many symptoms e.g. in epilepsy, spasmolysis, relief ofpain, influencing emesis, schizophrenia, migraine and also as ananxiolytic agent [Tarnawa, I. and Vizi, E. S., Restorative Neurol.Neurosci., 13, 41–57 (1998)].

The Hungarian Patent Application No. P 97 00688 and the correspondingGB-P No. 2 311 779 described, among others,1-(4-aminophenyl)-3-alkanoyl-4-methyl-3H-2,3-benzodiazepine derivativesthat might have contained also a chloro atom in position 7 and/or 8. Theknown compounds have antispasmodic, muscle relaxant and neuroprotectiveactivity and can be used for the treatment of neurological andpsychiatric disorders.

The scope of compounds claimed in the above patent includes2,3-benzodiazepines wherein the phenyl group being in position 1contains, in addition to the amino group in position 4, also a halo atomor a C₁₋₄ alkyl group in position 3. However, such compounds have notbeen examplified, and neither the identification data, nor thebiological effect thereof have been described.

In our animal experiments it was found that during the metabolism thattook place in the animal organism after the administration of the aboveknown compounds, at first, the amino group being in position 4 at thephenyl group in position 1 was acetylated. (Further on, in thedescription, it is called N-acetylation). Due to N-acetylation, thetherapeutical effect of the compounds is reduced. Since human beings canbe of fast or slow acetylator phenotype, it is difficult to determinethe proper therapeutical dose in the treatment. Therefore, the aim ofthe invention is to find 2,3-benzodiazepine derivatives characterized bydecreased rate of acetylation since in this case human beings of fastand slow acetylator phenotype, respectively, can be treated withessentially the same dose of active ingredient.

SUMMARY OF THE INVENTION

It was found that the above aim is achieved by the novel2,3-benzodiazepine derivatives of the formula

wherein

-   X represents a hydrogen atom, a chloro atom or a methoxy group,-   Y stands for a hydrogen atom or a halo atom,-   Z means a methyl group or a chloro atom,-   R is a C₁₋₄ alkyl group or a group of the formula —NR¹R²,    -   wherein    -   R¹ and R² represent, independently, a hydrogen atom, a C₁₋₄        alkyl group, a C₁₋₄ alkoxy group or a C₃₋₆ cycloalkyl group,        and pharmaceutically suitable acid addition salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is surprising that the above aim could be achieved by the compoundsof the invention wherein the phenyl group being in position 1 containedalso a methyl group or a chloro atom in ortho position relative to theamino group in position 4 since the ortho substitution reduced theN-acetylation significantly. Due to the hindered N-acetylation, someeffects of the novel compounds are stronger and longer lasting thanthose of the corresponding known compound in animal experiments.

Our experiences are supported by the following experiments in which theundermentioned novel compounds of the formula I and the corresponding1-(4-aminophenyl) analogues as known reference compounds have been used:

-   1=compound of Example 1 i.e.    3-acetyl-1-(4-amino-3-methyl-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,-   1a=1-(4-aminophenyl) analogue i.e.    3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,-   2=compound of Example 2 i.e.    1-(4-amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine,-   2a=1-(4-aminophenyl) analogue i.e.    1-(4-aminophenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine,-   3=compound of Example 3 i.e.    3-acetyl-1-(4-amino-3-chloro-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,-   3a=1-(4-aminophenyl) analogue i.e.    3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,-   4=compound of Example 4 i.e.    3-acetyl-1-(4-amino-3-methyl-phenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzo-diazepine,-   4a=1-(4-aminophenyl) analogue i.e.    3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzo-diazepine,-   5=compound of Example 5 i.e.    1-(4-amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine,-   5a=1-(4-aminophenyl) analogue i.e.    1-(4-aminophenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine.

Reduction of the rate of N-acetylation due to ortho substitution

Liver slices of Wistar rats were incubated in oxigenized Krebs-Ringersolution at 37° C. in the presence of 50 μM of 2,3-benzodiazepinederivative examined. 0.5 ml aliquots were taken at the beginning of theexamination, then after 30 and 60 minutes. Plasma proteins wereprecipitated with perchloric acid and, after alkalization, the2,3-benzodiazepine derivatives were extracted with chloroform. Thechloroform solutions were evaporated to dryness, the residue wasdissolved in the corresponding eluent. The 2,3-benzodiazepine derivativeused and the N-acetyl metabolite thereof were determined by highpressure liquid chromatography (Beckman System Gold HPLC, C-18reversed-phase column) using an UV detector (at 240 nm). Differenteluents were used for the optimal separation of the compounds. In caseof the compound according to Example 1 and the corresponding1-(4-amino-phenyl) analogue, the eluent consisted of a mixture of 50% of2 mM heptafluoro-butyric acid, 25% of methanol and 25% of acetonitrile.For the compound according to Example 3 and the corresponding1-(4-amino-phenyl) analogue, the eluent was a mixture of 50% of 2 mMheptafluorobutyric acid, 20% of methanol and 30% of acetonitrile. Forthe compound according to Example 4 and the corresponding1-(4-amino-phenyl) analogue, the eluent consisted of a mixture of 50% of2 mM heptafluorobutyric acid and 50% of acetonitrile.

The percentage of N-acetyl metabolite content of the sample taken at acertain time was calculated by dividing the hundredfold of the peak areaof the metabolite with the sum of the peak areas of the2,3-benzodiazepine derivative used and the N-acetyl metabolite. Theresults obtained are shown in Table 1 in which the concentrationsdetermined after 0, 30 and 60 minutes are indicated.

TABLE 1 Compound Amount of used Incubation N-acetyl (Example time inmetabolite No.) min. in % 1 0 0 1 30 2 1 60 6 1a 0 0 1a 30 18 1a 60 31 30 0 3 30 1 3 60 1 3a 0 0 3a 30 18 3a 60 31 4 0 0 4 30 0 4 60 4 4a 0 0 4a30 17 4a 60 31

From Table 1 it can be seen that the compounds of the formula I examinedare N-acetylated only at a negligible rate in 1 hour, in contrast to thecorresponding 1-(4-aminophenyl) analogues wherein the amount of theN-acetyl metabolite is, in general, 31% in 1 hour. Thus, the presence ofa methyl group or a chloro atom in ortho position relative to the aminogroup inhibits the N-acetylation of the amino group significantly.

Neuroprotective Effect in Magnesium Chloride Induced Global CerebralIschemia in Mice

The examination was carried out on groups consisting of 10 male NMRImice weighing 20–25 g. The compounds to be examined were dissolved in amixture of 5 volumes of 5M aqueous hydrochloric acid and 95 volumes ofwater, then the pH value of the solution was adjusted to 3 by theaddition of 1M aqueous sodium hydroxide solution. The solution obtainedwas administered intraperitoneally in a volume of 10 ml/kg. Eachcompound was tested at four increasing dose levels, and a further groupof animals was treated only with the vehicle (the latter was the controlgroup). 30 minutes after treatment, all mice received an intravenousinjection of saturated aqueous magnesium chloride solution in a volumeof 5 ml/kg. This injection caused an immediate cardiac arrest andcomplete cerebral ischemia. The increase in survival time (i.e. theinterval between the injection of magnesium chloride and the lastobservable gasp) was considered as a measure of the neuroprotectiveeffect according to Berga et al. [Berga, P. et al., Synergisticinteractions between piracetam and dihydroergocristine in some animalmodels of cerebral hypoxia and ischaemia, Arzneim. -Forsch., 36,1314–1320 (1986)]. Percentage changes in survival time were calculatedin comparison to that measured in the control group, and, from thevalues obtained, the dose prolonging survival by 50% (PD₅₀) wascalculated by linear regression analysis. The results obtained are shownin Table 2.

TABLE 2 Compound PD₅₀, (Example No.) in mg/kg 1 4.6 1a 10.4 4 9.0 4a11.0 5 12.3 5a 14.6

From Table 2 it can be seen that the PD₅₀ value of the compounds of theformula I examined is lower than that of the corresponding1-(4-aminophenyl) analogues. This means that the substituent being inortho position relative to the amino group enhances the neuroprotectiveeffect of the compounds.

Duration of Action in Rats as Assessed From the Decrease in Body CoreTemperature

One week prior to treatments, 6 male Wistar rats were anaesthetized byadministering 60 mg/kg of pentobarbital sodium [sodium5-ethyl-5-(1-methylbutyl)barbiturate]intraperitoneally. Using sterilesurgical procedures, TL11M2C50-PXT or TA10TA-F40 type radiotelemetrytransmitters (Data Sciences International, St. Paul, Minn., USA) wereimplanted into the peritoneal cavity of the animals. The transmitterspermitted continuous monitoring of the core body temperature. Afterimplantation, the rats were treated with an antibiotic(benzathine-benzylpenicillin was administered in a dose of 1 ml/kgi.m.). [The chemical name of benzathine-benzylpenicillin:[2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid]. The animals were housed individually in type 2 plastic rat cageswith free access to food and tap water.

The compounds to be examined were dissolved in a mixture of 5 volumes of5M aqueous hydrochloric acid and 95 volumes of water, then the pH valueof the solution was adjusted to 3 by the addition of 1M aqueous sodiumhydroxide solution. The solution obtained was administeredintraperitoneally in a volume of 10 ml/kg.

Radio signals emitted by the transmitters were detected by RLA1000 orRLA2000 type receivers placed under each cage. Data were collected andsaved by a Dataquest IV computerized data acquisition system. Thecomputer was set to sample body temperature for 10 seconds in everysecond minute. Mean values for 30 min. periods over the whole day werecalculated running the “sort utility” of the Dataquest IV system. Theupper and lower limits of the evaluating routine were set to excludebiologically improbable values. Individual body temperature curves wereaveraged for the 6 animals.

Peak effect (PE) was measured as the maximum decrease in bodytemperature in comparison to the last value prior to treatment (controlvalue). The PE values obtained are summarized in Table 3. Using the meanvalues, duration of action (D) of the compounds was determined. This isthe time interval from treatment to return of body temperature to thecontrol level. Values of D obtained are shown in Table 4.

TABLE 3 Compound (Example No.) PE, Δ° C. 1 −2.34 1a 2 −2.04 2a −1.87 4−3.09 4a −1.72

TABLE 4 Compound (Example No.) D in hour 1 20 1a 2 6 2a 4 4 19 4a 3.5

From the data of Tables 3 and 4 it can be seen that the maximum decreasein body temperature is larger and the duration of action is longer incase of the compounds containing a substituent in ortho positionrelative to the amino group. This means that the effect of the compoundsof the formula I is stronger and longer lasting than that of the knowncompounds.

The compounds of the formula I have antispasmodic, muscle relaxant andneuroprotective activities, and can be potentially used in the treatmentor prevention of any disease and symptom wherein the inhibition of thestimulant amino acid receptors is beneficial. Thus, the compounds of theinvention can be advantageously employed in any case wherein theAMPA/kainate non-competitive 2,3-benzodiazepine type antagonists areefficient, for example in the following diseases:

as a neuroprotective agent in symptoms accompanied by acute and chronicneurodegeneration, especially Parkinson's disease, Alzheimer's disease,amyotrophic lateral sclerosis, stroke, acute head injury, furthermorefor improving numerous symptoms for example in epilepsy, spasmolysis,relief of pain, in influencing emesis, in schizophrenia, in case ofmigraine and urination problems as well as for relieving the symptoms ofmedicine deprivation.

In the description and claims, under a halo atom especially a fluoroatom, chloro atom, bromo atom or iodo atom, preferably a chloro atom ismeant.

A C₁₋₄ alkyl group is a methyl group, ethyl group, isopropyl group,n-propyl group, n-butyl group, sec-butyl group, isobutyl group ortert.-butyl group, preferably a methyl group or ethyl group.

A C₁₋₄ alkoxy group is, in general, a methoxy group, ethoxy group,isopropoxy group, n-propoxy group or n-butoxy group, preferably amethoxy group.

A C₃₋₆ cycloalkyl group is, mostly, a cyclopropyl group, cyclopentylgroup or cyclohexyl group.

The pharmaceutically suitable acid addition salts of the2,3-benzodiazepine derivatives of the formula I are the non-toxic acidaddition salts of the compounds formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.or organic acids such as formic acid, acetic acid, fumaric acid, lacticacid, tartaric acid, succinic acid, citric acid, benzenesulfonic acid,p-toluenesulfonic acid, methane-sulfonic acid etc.

Due to the presence of a chiral centre, the compounds of the formula Ican be present in the form of optically active isomers and mixturesthereof. In the presence of certain substituents, geometrical isomerismor tautomerism may exist in the compounds of the formula I. Theinvention includes all the isomers of the 2,3-benzodiazepine derivativesof the formula I and any mixtures thereof.

Preferred 2,3-benzodiazepine derivatives are those wherein in formula I

-   X represents a chloro atom,-   Y stands for a hydrogen atom, a chloro atom or a bromo atom,-   R means a C₁₋₄ alkyl group,-   Z is a methyl group or a chloro atom,-   and pharmaceutically suitable acid addition salts thereof.

The especially preferred 2,3-benzodiazepine derivatives are thosewherein in formula I

-   X means a chloro atom,-   Y represents a hydrogen atom or a chloro atom,-   R stands for a methyl group,-   Z is a methyl group or a chloro atom,-   and pharmaceutically suitable acid addition salts thereof.

The compounds of the formula I can be prepared by the processes knownfrom Hungarian Patent Application No. P 97 00688. Suitably, a compoundof the formula I, wherein the amino group is replaced by a nitro group,is reduced in a manner known per se, for example with tin(II) chloride,sodium dithionite or by catalytical hydrogenation in the presence of aRaney nickel, palladium or platina catalyst using gaseous hydrogen,hydrazine, hydrazine hydrate, formic acid, a trialkylammonium formate ora sodium formate as the hydrogen source. The compound of the formula I,wherein the amino group is replaced by a nitro group, can be alsoprepared by the processes known from the Hungarian Patent ApplicationNo. P 97 00688.

Furthermore, the invention refers to a pharmaceutical compositioncontaining a 2,3-benzodiazepine derivative of the formula I or apharmaceutically suitable acid addition salt thereof as the activeingredient and one or more conventional carrier(s).

The pharmaceutical composition of the invention contains, in general,0.1 to 95 per cent by mass, preferably 1 to 50 per cent by mass,suitably 5 to 30 per cent by mass of the active ingredient.

The pharmaceutical composition of the invention is suitable for peroral,parenteral or rectal administration or for local treatment, and can besolid or liquid.

The solid pharmaceutical compositions suitable for peroraladministration may be powders, capsules, tablets, film-coated tablets,microcapsules etc., and can comprise binding agents such as gelatine,sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose,glucose, starch, calcium phosphate etc.; auxiliary substances fortabletting such as magnesium stearate, talc, poly(ethylene glycol),silica etc.; wetting agents such as sodium laurylsulfate etc. as thecarrier.

The liquid pharmaceutical compositions suitable for peroraladministration may be solutions, suspensions or emulsions and cancomprise e.g. suspending agents such as gelatine, carboxymethylcelluloseetc.; emulsifiers such as sorbitane monooleate etc.; solvents such aswater, oils, glycerol, propylene glycol, ethanol etc.; preservativessuch as methyl p-hydroxybenzoate etc. as the carrier.

Pharmaceutical compositions suitable for parenteral administrationconsist of sterile solutions of the active ingredient, in general.

Dosage forms listed above as well as other dosage forms are known perse, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co., Easton, USA (1990).

The pharmaceutical composition contains dosage unit, in general. Atypical dose for adult patients amounts to 0.1 to 1000 mg of thecompound of the formula I or a pharmaceutically suitable acid additionsalt thereof calculated for 1 kg body weight, daily. The daily dose canbe administered in one or more portions. The actual dosage depends onmany factors and is determined by the doctor.

The pharmaceutical composition is prepared by admixing a compound of theformula I or a pharmaceutically suitable acid addition salt thereof toone or more carrier(s), and converting the mixture obtained to apharmaceutical composition in a manner known per se. Useful methods areknown from the literature, e.g. Remington's Pharmaceutical Sciencesmentioned above.

A preferred pharmaceutical composition of the invention contains a2,3-benzodiazepine derivative of the formula I,

wherein

-   X represents a chloro atom,-   Y stands for a hydrogen atom, a chloro atom or a bromo atom,-   R means a C₁₋₄ alkyl group,-   Z is a methyl group or a chloro atom,    or a pharmaceutically suitable acid addition salt thereof as the    active ingredient.

The active ingredient of an especially preferred pharmaceuticalcomposition of the invention is a 2,3-benzodiazepine derivative of theformula I, wherein

-   X means a chloro atom,-   Y represents a hydrogen atom or a chloro atom,-   R stands for a methyl group,-   Z is a methyl group or a chloro atom,    or a pharmaceutically suitable acid addition salt thereof.

Furthermore, the invention refers to the use of the compounds of theformula I or pharmaceutically suitable acid addition salts thereof forthe preparation of a pharmaceutical composition of anxiolytic effect orsuitable for the treatment of symptoms accompanied by acute and chronicneurodegeneration, especially Parkinson's disease, Alzheimer's disease,amyotrophic lateral sclerosis, stroke, acute head injury, epilepsy andschizophrenia, for spasmolysis, relief of pain, influencing emesis,against migraine, for the treatment of urination problems or forrelieving the symptoms of medicine deprivation.

Likewise, the invention refers to a process for the treatment ofdiseases and symptoms listed above in which a therapeutically effectiveamount of a 2,3-benzodiazepine derivative of the formula I or apharmaceutically suitable acid addition salt thereof is administered toa patient being in need of the treatment.

The invention is further elucidated by means of the following Examples.

EXAMPLE 1(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzodiazepine

3.7 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl4-nitrophenyl)-3H-2,3-benzodiazepineare dissolved in a mixture of 75 cm³ of methanol and 38 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from ethanol. Thus, 1.67 g(49%) of the title compound are obtained in the form of pale yellowsolids melting at 180–182° C.

Analysis: for C₁₉H₂₀CIN₃O (341.844)

calculated: C, 66.76%; H 5.90%; N 12.29%; Cl 10.37%.

found: C 66.77%; H 5.92%; N 12.13%; Cl 10.13%.

¹H-NMR (CDCl₃): δ 7.48 (d, J=1.3 Hz, 1H), 7.35 (dd, J₁=2.1 Hz, J₂=8.1Hz, 1H), 7.28 (dd, J₁=2.0 Hz, J₂=8.2 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H),7.12 (d, J=2.2 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.21 (m, 1H), 4.01 (bs,2H), 2.79 (dd, J₁=5.5 Hz, J₂=13.7 Hz, 1H), 2.65 (dd, J₁=12.0 Hz, J₂=13.6Hz, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.30 (d, J=6.4 Hz, 3H).

¹³C-NMR (CDCl₃): δ 172.14, 169.21, 148.14, 138.46, 135.83, 132.35,131.43, 130.27, 129.40, 129.24, 128.72, 125.45, 121.79, 114.03, 60.47,38.28, 22.60, 18.32, 17.32.

EXAMPLE 2(±)-1-(4-Amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine

3.86 g (10 mmoles) of(±)-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepineare dissolved in a mixture of 80 cm³ of methanol and 13 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from acetonitrile. Thus, 1.99g (56%) of the title compound are obtained in the form of cream colouredsolids melting at 152–154° C.

¹H-NMR (CDCl₃): δ 7.47 (d, J=1.1 Hz, 1H), 7.34 (dd, J₁=2.1 Hz, J₂=8.1Hz, 1H), 7.29 (dd, J₁=2.0 Hz, J₂=8.2 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H),7.10 (d, J=2.2 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.21 (m, 1H), 4.01 (bs,2H), 2.78 (dd, J₁=5.6 Hz, J₂=13.7 Hz, 1H), 2.66 (˜t, J=12.9 Hz, 1H),2.47 (m, 1H), 2.20 (m, 1H), 2.20 )s, 3H), 1.30.(d, J=6.4 Hz, 3H), 1.04(t, J=7.5 Hz, 3H).

¹³C-NMR (CDCl₃): δ 172.46, 172.20, 154.48, 148.11, 138.54, 135.94,132.27, 131.39, 130.19, 129.36, 129.19, 128.60, 125.48, 121.76, 114.03,60.58, 38.29, 27.90, 18.34, 17.33, 8.77.

EXAMPLE 3(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzodiazepine

3.93 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-8-chloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 30 cm³ of methanol and 30 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from a mixture of ethylacetate and hexane. Thus, 1.03 g (30%) of the title compound areobtained in the form of yellow solids melting at 143–144° C.

Analysis: for C₁₈H₁₇Cl₂N₃O (362.262)

calculated: C 59.68%; H 4.73%, N 11.60%; Cl 19.57%.

found: C 59.09%; H 4.85%; N 11.24%; Cl 19.11%.

¹H-NMR (CDCl₃): δ 7.65 (d, J=1.9 Hz, 1H), 7.35 (m, 2H), 7.23 (d, J=8.2Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.23 (m, 1H),4.44 (bs, 2H), 2.83 (dd, J₁=5.1 Hz, J₂=13.9 Hz, ₁ H), 2.66 (dd, J₁=11.4Hz, J₂=13.8 Hz, 1H), 2.06 (s, 3H), 1.26 (d, J=6.4 Hz, 3H).

¹³C-NMR (CDCl₃): δ 169.88, 168.02, 145.71, 138.52, 135.15, 132.54,130.47, 130.37, 129.69, 129.27, 128.69, 126.81, 119.01, 114.88, 60.31,38.21, 22.68, 18.44.

EXAMPLE 4(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzodiazepine

4.06 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 55 cm³ of methanol and 55 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from a mixture ofethyl acetate and hexane. Thus, 3.27 g (87%) of the title compound areobtained in the form of yellow ochre solids melting at 127–129° C.

Analysis: for C₁₉H₁₉Cl₂N₃O (376.289)

calculated: C 60.65%; H 5.09%; N 11.17%; Cl 18.84%.

found: C 59.74%; H 5.07%; N 10.98%; Cl 18.62%.

¹H-NMR (CDCl₃): δ 7.45 (˜s, 1H), 7.39 (s, 1H), 7.28 (dd, J₁=2.0 Hz,J₂=8.2 Hz, 1H), 7.22 (s, 1H), 6.77 (d, J=8.3 Hz, 1H), 5.23 (m, 1H), 4.02(bs, 2H), 2.77 (dd, J₁=5.5 Hz, J₂=13.8 Hz, 1H), 2.65 (dd, J₁=11.8 Hz,J₂=13.5 Hz, 1H), 2.20 (s, 3H), 2.03 (s, 3H), 1.29 (d, J=6.4 Hz, 3H).

¹³C-NMR (CDCl₃): δ 169.40, 148.25, 139.93, 134.23, 134.08, 131.42,130.73, 130.56, 129.93, 129.15, 125.24, 121.86, 114.09, 60.07, 38.10,22.60, 13.80, 17.32.

EXAMPLE 5(±)-1-(4-Amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine

4.2 g (10 mmoles) of(±)-4,5-dihydro-7,8-dichloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepineare dissolved in a mixture of 40 cm³ of methanol and 40 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from acetonitrile. Thus, 1.99g (56%) of the title compound are obtained in the form of pale yellowsolids melting at 106–108° C.

Analysis: for C₂₀H₂₁Cl₂N₃O (390.316)

calculated: C 61.55%; H 5.42%; N 10.77%; Cl 18.17%.

found: C 60.68%; H 5.52%; N 10.47%; Cl 17.90%.

¹H-NMR (CDCl₃): δ 7.45 (d, J=1.1 Hz, 1H), 7.39 (s, 1H), 7.28 (dd, J₁=2.1Hz, J₂=8.3 Hz, 1H), 7.21 (s, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.22 (m, 1H),4.02 (bs, 2H), 2.77 (dd, J₁=5.6 Hz, J₂=13.8 Hz, 1H), 2.64 (dd, J₁=11.9Hz, J₂=13.6 Hz, 1H), 2.47 (m, 1H), 2.20 (m, 1H), 2.20 (s, 3H), 1.30 (d,J=6.4 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H).

¹³C-NMR (CDCl₃): δ 172.63, 171.10, 148.22, 140.02, 134.20, 131.40,130.66, 130.44, 129.90, 129.12, 125.28, 121.86, 114.10, 60.21, 38.12,27.92, 18.32, 17.34, 8.77.

EXAMPLE 6(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzodiazepine

4.26 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 40 cm³ of methanol and 40 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from acetonitrile.Thus, 2.80 g (71%) of the title compound are obtained in the form ofbutter coloured solids melting at 127–129° C.

Analysis: for C₁₈H₁₆C₃N₃O (396.707)

calculated: C 54.50%; H 4.07%; N 10.59%; Cl 26.81%.

found: C 54.26%; H 4.14%; N 10.48%; Cl 26.28%.

¹H-NMR (CDCl₃): δ 7.62 (d, J=1.9 Hz, 1H), 7.39 (s, 1H), 7.32 (dd, J₁=2.0Hz, J₂=8.4 Hz, 1H), 7.22 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.25 (m, 1H),4.48 (bs, 2H), 2.82 (dd, J₁=5.1 Hz, J₂=13.9 Hz, 1H), 2.66 (dd, J₁=11.2Hz, J₂=13.8 Hz, 1H), 2.07 (s, 3H), 1.25 (d, J=6.4 Hz, 3H).

¹³C-NMR (CDCl₃): δ 170.03, 166.60, 145.80, 139.93, 134.45, 133.34,130.88, 130.52, 130.29, 130.18, 129.17, 126.53, 119.00, 114.88, 59.79,37.99, 22.68, 18.42.

EXAMPLE 7(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

4.46 g (10 mmoles) of(±)-3-acetyl-7-bromo4,5-dihydro-1-(3-methyl-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepineare dissolved in 190 cm³ of methyl cellosolve, then 2.1 g (15 mmoles) ofpotassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and,under vigorous stirring, 1.95 cm³ (40 mmoles) of 98% hydrazine hydrateare added. The reaction mixture is stirred at 100° C. for 1 hour, thecatalyst is filtered, the filtrate is evaporated, and the residue isrubbed with 50 cm³ of water to obtain solid matter. The crude product ispurified by chromatography over a column containing silica gel and usinga mixture of ethyl acetate and hexane, then the product isrecrystallized from acetonitrile. Thus, 1.6 g (47%) of the titlecompound are obtained in the form of cream coloured solids melting at169–171° C.

Analysis: for C₂₀H₂₃N₃O₂ (337.425)

calculated: C 71.19%; H 6.87%; N 12.45%.

found: C 71.69%; H 6.74%; N 12.34%.

¹H-NMR (CDCl₃): δ 67.51 (bs, 1H), 7.33 (dd, J₁=1.8 Hz, J₂=8.1 Hz, 1H),7.19 (d, J=8.4 Hz, 1H), 6.91 (dd, J₁=2.9 Hz, J₂=8.4 Hz, 1H), 6.65 (d,J=8.1 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 5.18 (m, 1H), 3.97 (bs, 2H), 2.72(m, 1H), 2.61 (m,1H), 2.19 (s, 3H), 2.01 (s, 3H), 1.31 (d, J=6.6 Hz,3H).

¹³C-NMR (CDCl₃): δ 168.89, 158.06, 147.91, 135.19, 132.25, 131.59,129.36, 129.02, 125.98, 121.67, 115.67, 114.79, 114.00, 60.69, 55.49,38.03, 22.59, 18.32, 17.29.

EXAMPLE 8(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

4.66 g (10 mmoles) of(±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepineare dissolved in 190 cm³ of methyl cellosolve, then 2.1 g (15 mmoles) ofpotassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and,under vigorous stirring, 1.95 cm³ (40 mmoles) of 98% hydrazine hydrateare added. The reaction mixture is stirred at 90° C. for 0.5 hours, thecatalyst is filtered, the filtrate is evaporated, and the residue isrubbed with 50 cm³ of water to obtain solid matter. The crude product ispurified by chromatography over a column containing silica gel and usinga mixture of ethyl acetate and hexane, then the product isrecrystallized from ethanol. Thus, 1.1 g (30%) of the title compound areobtained in the form of white solids melting at 152–155° C.

Analysis: for C₁₉H₂₀CIN₃O₂ (357.840)

calculated: C 63.77%; H 5.63%; N 11.74%; Cl 9.91%.

found: C 63.70%; H 5.61%; N 11.51%; Cl 9.86%.

¹H-NMR (CDCl₃): δ 7.67 (d, J=1.8 Hz, 1 H), 7.41 (dd, J₁=1.8 Hz, J₂=8.1Hz, 1H), 7.20 (d, J=8.4 Hz, 1 H), 6.93 (dd, J₁=2.6 Hz, J₂=8.1 Hz, 1H),6.77 (d, J=8.4 Hz, 1H), 6.64 (d, J=2.9 Hz, 1H), 5.20 (m, 1H), 4.46 (bs,2H), 3.75 (s, 3H), 2.80 (dd, J₁=5.1 Hz, J₂=13.9 Hz, 1H), 2.63 (dd,J₁=11.7 Hz, J₂=13.9 Hz, 1H), 2.05 (s, 3H), 1.29 (d, J=6.2 Hz, 3H).

¹³C-NMR (CDCl₃): δ 158.12, 145.56, 134.48, 132.25, 130.55, 129.38,129.28, 118.86, 115.84, 114.80, 114.68, 60.66, 55.49, 37.91, 22.67,18.42.

EXAMPLE 9(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-7-chloro-4-methyl-3H-2,3-benzodiazepine

3.7 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7-chloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 80 cm³ of methanol and 33 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from a 1:2 mixture ofethyl acetate and hexane. Thus, 2.88 g (84%) of the title compound areobtained in the form of yellow ochre solids melting at 200–205° C.

Analysis: for C₁₉H₂₀ClN₃O (341.844)

calculated: C 66.76%; H 5.90%; N 12.29%; Cl 10.37%.

found: C 65.63%; H 6.07%; N 12.03%; Cl 10.58%.

¹H-NMR (CDCl₃): δ 7.45 (s, 1H), 7.28 (m, 3H), 7.07 (d, J=8.2 Hz, 1H),6.66 (d, J=8.2 Hz, 1H), 5.24 (m, 1H), 4.00 (bs, 2H), 2.77 (dd, J₁=5.6Hz, J₂=13.7 Hz, 1H), 2.68 (t, J=12.8 Hz, 1H), 2.18 (s, 3H), 2.01 (s,3H), 1.31 (d, J=6.3 Hz, 3H).

¹³C-NMR (CDCl₃): δ 172.54, 169.11, 148.08, 141.85, 136.09, 132.62,131.54, 130.32, 129.16, 128.22, 126.63, 125.68, 121.69, 114.00, 60.30,38.67, 22.55, 18.34, 17.29.

EXAMPLE 10(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-7-bromo4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

4.66 g (10 mmoles) of(±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepineare dissolved in a mixture of 45 cm³ of methanol and 45 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by boiling in 50 ml ofacetonitrile. Thus, 3.52 g (81%) of the title compound are obtained inthe form of white solids melting at 235–237° C.

Analysis: for C₁₉H₁₉BrCIN₃O₂ (436.740)

calculated: C 52.25%; H 4.39%; N 9.62%; ΣHIg(Cl) 16.24%.

found: C 51.04%; H 4.34%; N 9.39%; ΣHIg(Cl) 16.16%.

¹H-NMR (CDCl₃): δ 7.65 (d, J=1.8 Hz, 1H), 7.48 (s, 1H), 7.36 (dd, J₁=1.8Hz, J₂=8.3 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 5.21 (m, 1H),4.46 (bs, 2H), 3.77 (s, 3H), 2.77 (dd, J₁=5.1 Hz, J₂=14.1 Hz, 1H), 2.62(dd, J₁=11.4 Hz, J₂=13.9 Hz, 1H), 2.07 (s, 3H), 1.25 (d, J=6.3 Hz, 3H).

¹³C-NMR (CDCl₃): δ169.77, 168.18, 154.48, 145.64, 133.71, 133.50,133.04%, 130.45, 129.25, 126.94, 118.89, 114.81, 114.08, 112.42, 60.48,56.52, 37.54, 22.74, 1843.

1. A compound of the formula (I)

wherein, X represents a hydrogen atom, a chloro atom or a methoxy group,Y stands for hydrogen atom or a halo atom, Z means a methyl group or achloro atom, R is a C₁₋₄ alkyl group or a group of the formula —NR¹R²,wherein R¹ and R² represent, independently, a hydrogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group or a C₃₋₆ cycloalkyl group, andpharmaceutically suitable acid addition salts thereof.
 2. The compoundaccording to claim 1, wherein X represents a chloro atom, Y stands for ahydrogen atom, a chloro atom or a bromo atom, R means a C₁₋₄ alkylgroup, and pharmaceutically acceptable acid addition salts thereof. 3.The compound according to claim 2, wherein Y represents a hydrogen atomor a chloro atom, R stands for a methyl group, and pharmaceuticallyacceptable acid addition salts thereof.
 4. A pharmaceutical compositioncomprising the compound according to claim 1, or a pharmaceuticallysuitable acid addition salt thereof as the active ingredient in additionto the usual carrier(s).
 5. The pharmaceutical composition according toclaim 4, wherein in the compound of formula (I), X represents a chloroatom, Y stands for a hydrogen atom, a chloro atom or a bromo atom, Rmeans a C₁₋₄ alkyl group.
 6. The pharmaceutical composition according toclaim 5, wherein in the compound of formula (I), Y represents a hydrogenatom or a chloro atom, R stands for a methyl group.
 7. A method oftreating diseases and symptoms accompanied by acute and chronicneurodegeneration, which comprises: administering a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically suitable acid addition salt thereof to a patient inneed thereof, wherein said symptoms accompanied by acute and chronicnuerodegeneration comprise symptoms attributable to Parkinson's disease,Alzheimer's disease, amyotrophic lateral sclerosis, stroke, acute headinjury, epilepsy, schizophrenia, spasmolysis, emesis, migraine,urination problems or medicine deprivation.